Nitric oxide (NO) is a messenger molecule that regulates macrophage killing of tumor cells and bacteria (C. F. Nathan and J. B. Hibbs, Jr., Curr. Opin. Immunol. 3, 65 (1991)), blood vessel relaxation (S. Moncada, R. M. J. Palmer, E. A. Higgs, Pharmacol. Rev. 43, 109 (1991); L. J. Ignarro, Ann. Rev. Pharmacol. Toxicol. 30, 535 (1990)) and also is a neurotransmitter (D. S. Bredt and S. H. Snyder, Neuron 8, 3 (1992)). When formed in high quantities in response to actions of the excitatory neurotransmitter glutamate acting at N-methyl- D-aspartate (NMDA) receptors. NO mediates neuronal killing (V. L. Dawson et al., Proc. Natl. Acad. Sci. U.S.A. 88, 6368 (1991); V. L. Dawson et al., J. Neurosci. 13, 2651 (1993)). Toxicity due to NMDA accounts for neural damage in vascular stroke, as NO synthase (NOS) inhibitors prevent stroke damage (J. P. Nowicki, D. Duval, H. Poignet, B. Scatton, Eur. J. Pharmac. 204, 339 (1991)). Mechanisms proposed for NO neurotoxicity as well as tumoricidal and bactericidal actions include mono-ADP-ribosylation and S-nitrosylation of glyceraldehyde-3-phosphate dehydrogenase (J. Zhang and S. H. Snyder, Proc. Natl. Acad. Sci. U.S.A. 89, 9382 (1992); A. Y. Kots et al., FEBS Lett. 300, 9 (1992); S. Dimmeler, F. Lottspeich, B. Brune, J. Biol. Chem. 267, 16771 (1992); L. Molina y Vedia et al., J. Biol. Chem. 267, 24929 (1992)), inhibition of mitochondrial enzymes such as cis-aconitase (J. -C. Drapier and J. B. Hibbs, Jr., J. Clin. Invest. 78, 790 (1986)), inhibition of the mitochondrial electron transport chain (Nathan and Hibbs, supra), inhibition of ribonucleotide reductase (Lepoivre, B. Chenais, A. Yapo, G. Lemaire, J. Biol. Chem. 265, 14143 (1990); N. S. Kwon, D. J. Stuehr, C. F. Nathan, J. Exp. Med. 174, 761 (1991)), and DNA damage (D. A. Wink et al., Science 254, 1001 (1991); T. Nguyen et al., Proc. Natl. Acad. Sci. U.S.A. 89, 3030 (1992)). DNA damage activates poly(ADP-ribose) synthetase (PARS, EC 2.4.2.30) (G. de Murcia, J. Menissier-de Murcia, V. Schreiber, BioEssays 13,455 (1991); J. E. Cleaver and W. F. Morgan, Mutation Res. 257, 1 (1991); J. C. Gaal, K. R. Smith, C. K. Pearson, Trends in Biological Sciences 12, 129 (1987); N. A. Berger, Rad. Res. 101, 4 (1985)). PARS is a nuclear enzyme which, upon activation by DNA strand breaks, adds up to 100 ADP-ribose units to nuclear proteins such as histones and PARS itself.
There is a continuing need in the art for effective methods of preventing, treating or ameliorating diseases caused by NMDA neurotoxicity, such as vascular stroke, Alzheimer's disease, Huntington's disease, and Parkinson's disease.